U.S. patent number 7,033,499 [Application Number 10/777,088] was granted by the patent office on 2006-04-25 for flexible disposable vessel.
This patent grant is currently assigned to ILC Dover LP. Invention is credited to Donald R. Cohee, Ajay K. Prasad.
United States Patent |
7,033,499 |
Cohee , et al. |
April 25, 2006 |
Flexible disposable vessel
Abstract
A disposable flexible vessel contains a septum, dividing a first
chamber from a second chamber. By flowing a fluid through the
septum, the fluid is treated as it moves from the first chamber to
the second chamber. The particular configuration of the septum
allows for treatments such as mixing, reacting, heating, and
cooling, as well as filtering of the fluid.
Inventors: |
Cohee; Donald R. (Felton,
DE), Prasad; Ajay K. (Newark, DE) |
Assignee: |
ILC Dover LP (Frederica,
DE)
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Family
ID: |
32869587 |
Appl.
No.: |
10/777,088 |
Filed: |
February 13, 2004 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20040159616 A1 |
Aug 19, 2004 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60447011 |
Feb 13, 2003 |
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Current U.S.
Class: |
210/321.75;
210/416.1; 210/472; 210/488; 424/422; 604/406; 604/408;
604/409 |
Current CPC
Class: |
A61L
2/0035 (20130101); A61L 2/26 (20130101); B01D
15/00 (20130101); B01D 61/142 (20130101); B01D
61/18 (20130101); B01D 61/20 (20130101); B01D
63/08 (20130101); B01D 63/16 (20130101); B01D
69/02 (20130101); B01F 5/0683 (20130101); B01F
5/0688 (20130101); B01F 11/0017 (20130101); B01F
15/00948 (20130101); B01F 15/0205 (20130101); B01F
15/0212 (20130101); B01F 15/0223 (20130101); B01J
19/18 (20130101); A61L 2/022 (20130101); A61L
2202/122 (20130101); A61L 2202/21 (20130101); B01F
2215/0032 (20130101); B01F 2215/005 (20130101) |
Current International
Class: |
B01D
63/00 (20060101) |
Field of
Search: |
;210/321.6,416.1,321.75,321.84,767,321.68,321.64,321.67,488-490,472
;604/4,408,5.01,6,114,409 ;424/472 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Fortuna; Ana
Attorney, Agent or Firm: Stevens, Davis, Miller &
Mosher, L.L.P.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims domestic priority of provisional
application Ser. No. 60/447,011, filed Feb. 13, 2003, the entire
disclosure of which is herein incorporated by reference in its
entirety.
Claims
What is claimed is:
1. A vessel comprising at least one flexible wall joined to either
a first end or a second end, and a septum spaced intermediate said
first and second ends, said septum being attached to said flexible
walls, wherein at least one of said first end and said second end
comprises a isolator film and a further septum, such that removal
of said isolator film exposes said further septum.
2. The vessel of claim 1, wherein said vessel comprises at least
one port for introducing or removing components.
3. The vessel of claim 1, wherein the septum further comprises at
least one selected from the group consisting of micropores, a
vacuum device, and moveable tubes embedded therein.
4. The vessel of claim 1, wherein the septum comprises at least one
selected from the group consisting of fabric, metal, plastic and
ceramic.
5. The vessel of claim 1, wherein the septum is rigid.
6. The vessel of claim 1, wherein said septum has an open area, as
a percentage of total area of said septum, between approximately 10
and approximately 90%.
7. The vessel of claim 1, further comprising at least one perfusion
filter positioned in said vessel.
8. A device comprising the vessel of claim 1, wherein the vessel is
located on a rocking platform.
9. A vessel comprising at least one flexible wall joined to either
a first end or a second end, and a septum spaced intermediate said
first and second ends, said septum being attached to said at least
one flexible wall, wherein said septum is relatively moveable with
respect to said first and second ends.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a flexible, sterile, sealable or sealed
and at least partially or completely disposable vessel for
performing any or all of mixing, heating, cooling, filtering,
separating, forming cakes, drying, fermenting, blending powders,
reacting chemicals and storing, which can be done with or without a
gaseous head. Such vessels may be used (or, in some cases, re-used)
as (1) a storage container optionally with heating/cooling with the
optional application of mixing; or (2) a small flexible mixer that
can be actuated by hand, in mechanical situations as needed, such
as in mixing paint.
2. Description of the Related Art
Improving processes to make various chemical compounds, such as
powder, is a major focus of the pharmaceutical industry. With the
rising costs of the drugs and other products or chemicals,
manufacturers of such items have looked to innovation and mass
production to reduce the manufacturing costs and streamline
processes. However, there continues to be the costs and attendant
disadvantages of maintaining "clean rooms" so as to prevent the
introduction of contaminants into the process as well as the need
to protect workers with at least one of protective masks, suits, or
other protection equipment because of the potential risk of
exposure to the reactants and/or products of such processes.
Additionally, cleaning and certification or validation of equipment
and piping tends to greatly increase costs.
In addition, conventional chemical processing has used separate
equipment to perform a single function, e.g., a mixing vessel is
distinct from a reactor or filter. However, by the disclosed
invention, it is possible to perform multiple unit operations of
chemical processes in a single vessel.
Conventional manufacturing, mixing and/or stirring systems have
been used in this type of industry for a considerable period of
time. In a typical pharmaceutical powder production system for
example, the various ingredients or components are introduced into
an array of rigid vessels each of which perform some single
function. FIG. 1 illustrates a typical process. Chemicals or
components are introduced into a mixer 110 where they are mixed by
a known method, e.g., a stirrer. The mixture is then transferred
into one or more reactors 120, which causes a reaction of the
components by heat, pressure, etc. and other components may be
added as well. Following the reaction, the material is again
transferred to a centrifuge 130 for separation of undesired
material. Finally, the material is dried in a dryer 140 to remove
liquid components and form the desired powder, which is again
transferred to a storage location 150.
Another and more complicated system for a typical biopharmaceutical
process is illustrated in FIG. 2. It generally has a similar
step-by-step process as the process outlined above, but with more
separated locations to perform certain processes. For example, the
system has a pair of media mixers 200, a pair of fermenters 210,
several filtration vessels 230, which may be microfiltration
vessels, ultrafiltration vessels, sterile filtration vessels, etc.,
dialfiltration buffer vessels 240, and chromatography buffer
vessels 250. Additionally, each of the vessels has at least a pair
of ports for addition of other material as well as removal of waste
material. The whole system yields a multitude of vessels for the
production of a single desired material.
Other problems associated with these processes is with the
multitude of vessels and transference means is the likelihood of
leaks in the system, undesired material entering the system,
material from a previous process remaining in the vessel which
interferes with a subsequent process, etc.
When a large scale production is required, the glass beaker of
laboratory scale may be replaced by a large metal vat or other
conventional industrial vessel that also provides heating and
cooling capacity. In either system, the components are sequentially
or consecutively added to the vessel where the mixing and/or
stirring is conducted. In such systems, a stirring device is
generally inserted through the upper, open face of the container
and powered from an external source. Additionally, reuse of the
conventional system requires significant cleaning and sterilization
processes to ensure the absence of undesirable materials. The
associated costs of cleaning/sterilization and recertification of
the equipment prior to reuse is a major disadvantage of the prior
art avoided by the present inention.
Furthermore, the traditional beaker of the laboratory or the
industrial vat mixing systems require intervention between the
beaker and the mixing means, which can also introduce contaminants
and render the process less efficient. Examples include those
described in U.S. Pat. Nos. 5,941,635 and 4,114,522, each of which
is herein incorporated by reference in its entirety.
Other designs require sophisticated manipulation of the vessel to
mix the material contained therein by rocking the vessel about an
axis, such as those disclosed in U.S. Pat. No. 6,190,913. Still
further designs require the user to mix the material by squeezing a
flexible vessel, such as that disclosed in U.S. Pat. No. 5,795,330.
Other designs use passing a fluid through a mixing disk, such as
those shown in U.S. Pat. Nos. 5,868,495 and 6,447,158. Finally,
others oscillate the mixing disk through the fluid, such as those
shown in U.S. Pat. Nos. 4,966,468 and 4,436,458. However, such
mixing apparatus are rigid structures and do not effectively reduce
the multitude of vessels require to perform a single process.
As a result of the streamlining of the process to make materials,
the biopharmaceutical process industry needs technologies that use
disposable manufacturing components versus stainless steel tanks
and piping. An example of such a vessel is disclosed in the
co-pending application U.S. Ser. No. 10/256,070 filed Sep. 27,
2002, which is assigned to the present assignee and is herein
incorporated by reference in its entirety. However, such methods
and apparatus disclosed therein require the use of several
disposable vessels for the production of a typical material.
SUMMARY OF THE INVENTION
An object of the invention is to overcome the problems outlined
above using traditional vessels in production of pharmaceutical
materials, biopharmaceutical materials, chemicals, chemical
formulations, and other various materials. Another object of
invention is to reduce the number of vessels needed in such a
production process. A further object is to reduce the likelihood of
entrance of contaminants into the vessels during the production
process. A still further object is to eliminate the costs
associated with cleaning, sterilization and revalidation of a
vessels and piping used in the foregoing industries.
These problems as well as others are overcome using a mechanically
actuated flexible containment vessel that is configured to perform
various manufacturing processes. The vessel comprises a high
strength flexible polymer or coated fabric with low extractables,
chemical compatibility and may operate over a broad
operating/storage temperature range. The vessel should have a very
low bio-burden, i.e., not support biogrowth and be sterilizable and
preferably disposable by incineration. Exemplary materials are the
olefins, especially polyethylene, and fluorocarbon polymers, such
as PTFE. In one embodiment, the vessel has a generally two-tiered
design with an upper and lower chamber and an upper and lower disk
at either end and one center septum dividing the vessel into two
portions creating the chambers. At an appropriate filling of the
vessel with materials to be processed, e.g., full half of a chamber
to allow run length for moving the center septum, the center septum
relatively moves between a position adjacent to the upper disk and
a position adjacent to the lower disk. The center septum also has a
series of holes to allow the material to pass from the upper
chamber to the lower chamber. A back and forth movement of the
center septum relative to the contents of the vessel forces the
material to pass through the septum which stirs the material
contained therein. Sterility of the contents is maintained via the
use of sterile entry and exit ports on the device. Alternatively,
components to be manipulated may be prepackaged in repturable bags
or other frangible containers during manufacture of the vessel. In
use, the component container is ruptured or otherwise opened to
release the contents thereof. In another embodiment, the septum
contains a, e.g., frangible membrane. Rupture of the frangible
membrane, through a physical manipulation, heat, chemical or other
means, allows the fluid(s) contained in the vessel to contact the
active portions of the septum. Prior to rupturing of the membrane,
the fluid or fluids are maintained separately, as the membrane
prevents interaction with both the septum and the other fluid.
Additionally, although the location of the septum has been
described as being in the "center," it should be understood that
any location between the interior upper and lower surfaces is
sufficient.
In another embodiment, the septum is provided with a series of
flutes therein that allows for hot or cold fluid to pass. As the
septum is oscillated in the vessel, the temperature of the fluid
passing through the septum is transferred to the material in the
vessel to heat or cool the material as desired.
In a further embodiment, the center septum is provided with a
series of passageways that terminate inside the vessel to allow
addition of chemicals or other materials. For example, the vessel
can be used as a fermentation vessel where make-up solutions are
added to the material in the vessel followed by the addition of
lysing solutions. The material can be left to ferment in the vessel
and additionally left in the vessel for storage.
In a still further embodiment, the vessel is used as a reactor
whereby the upper and lower septums are pressed together with a
certain pressure by a pair of reactor plates or a pressurization
system. The pressure created in the material within the vessel aids
in reacting the materials therein. The center septum may also be
provided with heated or cooled fluid to change the temperature of
the material and may also continue mixing oscillations.
In an additional embodiment, the vessel may be used as a cross flow
filtration apparatus, whereby the surface of the center septum
located within the vessel is provided with a microporous coating
having a vacuum source therein. Upon a mixing oscillation of the
center septum, turbulent conditions are created within the vessel
allowing the coating, in conjunction with the suction force or
pressure, to filter out a desired particulate.
Additionally, the vessel may be used as a microfiltration vessel
whereby an additional center septum is introduced into the chambers
having a micro-filter. Following a mixing, heating, reacting of the
material in the vessel, the material is passed through the
micro-filter to remove a desired particulate or other material.
In a still further embodiment, the vessel according to the
invention may be used to express a slurry into a cake. A cake
fabric filter is introduced into the upper chamber of the vessel
followed by an addition of slurry into the upper chamber. Through a
series of manipulations of the center septum and lower disk and a
filtering of liquid discharge through the cake filter and up
through a vessel discharge line, the slurry is reduced to a cake. A
similar process may be used to clean the cake.
In an additional embodiment, the vessel may be used to dry the cake
following the above process or undry cake may be introduced into
the vessel. In this embodiment, a microwave heater is placed on or
under a reactor plate on the bottom of the vessel and a vent line
is provided on an upper surface of the vessel exiting the chambers.
Further, either the center septum has a wire grid design or an
additional center septum is provided with such a wire grid design.
The grid breaks up the cake material with movement of the septum
and the heater dries the cake. The moisture and gas are removed
from the vent line to dry the cake.
To remove the material from the vessel, a discharge chute is
provided on a bottom surface thereof whereby the material may be
drained or squeezed out of the vessel by kneading the vessel walls
or collapsing the vessel. A bag out sleeve may be provided for the
purpose of capturing vessel contents at a discrete time during the
process for purposes of sampling or certifying the contents of the
vessel. For example, in a process where the reaction is time
dependent, a portion of the reactants/products can be expressed
into the bag out sleeve, the sleeve sealed behind the sample, e.g.,
heat sealed and the sample analyzed to determine the progress of
the reaction. The bag out sleeve may, thus, be used to capture a
number of samples at different times without exposing the contents
of the vessel to the outside environment or workers.
The vessel may have other designs and structures that use the
multiple chambered vessel design as outlined above and have the
above-described characteristics. For example, the vessel may be
cylindrical shaped, cubic, polygonal such as square, pentagonal,
hexagonal, etc.; rectangular, conical, trapezoidal, accordion
style, angularly collapsible, and other shapes that are capable of
providing the features outlined above.
BRIEF DESCRIPTION OF THE DRAWINGS
The embodiments, features and advantages of the invention described
herein will occur to those skilled in the art from the following
description of a preferred embodiment and the accompanying
drawings, in which:
FIG. 1 is a diagram of a conventional pharmaceutical powder
production process;
FIG. 2 is a diagram of a conventional biopharmaceutical
process;
FIG. 3 illustrates a vessel according to a preferred embodiment of
the present invention;
FIG. 4 illustrates a cut-away view of the vessel shown in FIG. 3
showing the inner chambers;
FIG. 5 illustrates a septum of the vessel shown in FIG. 3;
FIGS. 6A-6B illustrate a cut-away view of the vessel showing a
mixing motion;
FIG. 6C illustrates the vessel shown in FIG. 3 filled half full
with the gas head partially removed;
FIG. 7A illustrates another embodiment of the septum having a
heating system therein;
FIG. 7B illustrates a cross sectional view of the septum shown in
FIG. 7A along line 7A--7A;
FIG. 7C illustrates another embodiment of the heating system in the
septum;
FIG. 7D illustrates a cross sectional view of the septum shown in
FIG. 7C along line 7B--7B;
FIG. 8 illustrates a cut away view of the vessel according to
another embodiment of the invention having means for a reacting
material;
FIGS. 9A and 9B illustrate another embodiment of the septum having
additional means to add other materials into the vessel for
fermentation or other processes;
FIG. 10A illustrates another embodiment of the septum incorporating
a micro/ultrafiltration system;
FIG. 10B illustrates a cross sectional view of the septum shown in
FIG. 10A along line 10A--10A;
FIG. 10C illustrates a cross sectional view of the septum shown in
FIG. 10A along line 10B--10B;
FIGS. 11A-11E illustrate a cut-away view of the vessel according to
another embodiment of the invention showing a system and method for
making and cleaning cakes from a slurry;
FIGS. 12A-12D illustrate a septum and a cut-away view of the vessel
according to another embodiment of the invention showing a system
and method for drying cakes;
FIGS. 13A-13C illustrate a septum and a cut-away view of the vessel
according to another embodiment of the invention showing a system
and method for microfiltration of material;
FIGS. 14A-14B illustrate a discharge means for the vessel according
to the invention; and
FIGS. 15A-15F illustrate differing designs and shapes possible for
the vessel according to the invention.
FIG. 16 illustrates a modification of the system to include
flexible, thin walled tubes with flared ends mounted in the holes
of the septum for relative movement therethrough.
FIG. 17 shows a further modification of the septum to have the
holes therethrough positioned at angles other than 90.degree.
through the septum so as to induce swirling motions.
FIG. 18 shows a further modification of the septum/vessel design
such that the septum does not have a strictly up and down motion
with regard to the contents of the vessel but, rather, a tilting
motion.
FIG. 19A shows a further modification of the mixing process where
the vessel is rocked along its longitudinal axis.
FIG. 19B shows a different embodiment of a rocking vessel.
FIG. 20 illustrates the use of two pistons connected to the septum
to provide movement of the septum through the contents of the
vessel.
FIG. 21 is a graph which shows that the shape of the bottom of the
vessel influences mixing speed.
FIG. 22 is a modification of FIG. 2 showing how the invention can
reduce the apparatus required in FIG. 2 to 5 modules.
FIGS. 23A-E shows the bioreactor module of FIG. 22 in detail, and
at various stages of different unit operations.
DETAILED DESCRIPTION OF THE INVENTION
The principle embodiment of the invention is shown in FIGS. 3-6. In
FIG. 3, a general design of a vessel 10 is shown. It has a
generally cylindrical shape and preferably made of a high strength
flexible coated fabric. Although certainly not required in every
embodiment of the invention, in some applications it is possible
that the vessel be transparent to permit photo initiation, or
observation, e.g., highly viscous materials. In any event, it is
preferred that the material be reinforced, e.g., a film reinforced
by a fabric. It has an upper disk 510 and a lower disk 520 that
form the upper and lower planes of the cylindrical shape. Vessel 10
also has a septum 500 subdividing the cylinder and parallel to
upper and lower disks 510 and 520 thereby dividing the vessel into
two portions, an upper portion and a lower portion, having side
walls 530 and 540, respectively. The portions may be of equal or
different volumes. The disks and the vessel walls are integrated at
corners 301 via either an adhesive, overlapping of material,
thermally or sonic welding, or the material from each section is
integrated into the adjacent section (molding) to provide strong
joints at the corners to prevent tearing and provide a strong seal.
The volume of the vessel can easily be scaled up from laboratory to
pilot plant to commercial processing and sizes of up to 20,000
liters and more are feasible.
The disks and vessel walls may also be integrated via a clamping
system, as shown in FIG. 7D, which discloses a hybrid vessel 10,
whereby some or all of the septums and disks are rigid. An example
is a rigid heating/cooling septum 500, described below. As shown,
septum 500 is provided with a clamp base 750 integrated thereon.
Clamp base 750 has a clamp ring 751 and a clamp bolt 752 mounted
thereon. A portion of upper wall 530 is pulled between clamp ring
751 and clamp base 750. Clamp bolt 752 is tightened to secure the
material of side wall 530 therein. The clamping system provides a
solid clamp the full circumference of septum 500 to effectively
secure side wall 530 to septum 500, and provide a clamp sufficient
to prevent material or other fluids from entering or exiting vessel
10. Similar clamping systems may be used for upper and lower disk
510 and 520 as well.
Upper and lower disks 510 and 520 and the septum 500 have generally
a planar design. Each has an outer ring, 511, 521 and 501,
respectively which is generally a bead around the surface of the
disk. These outer rings can be made of fabric, plastic, metal or
other material and can be either stiff or flexible. They can be
used for gripping vessel 10 or for securing a particular disk.
Across the center of each disk inside its outer ring are flexible
fabric material layers 512, 502 and 522. The flexible fabric may
comprise the entire disk center or the disk may have a rigid core,
made out of a plastic or metal surrounded by such material. The
disks may also be made solely of the metal or plastic to create a
rigid disk. For purposes of this description, the flexible fabric
disks are described.
The fabric of each vessel and the disks is formed of a chemically
compatible fabric with low extractables and has a broad temperature
operating range. The fabric must have a sufficient material
strength to be used in pressure applications. For high temperature
applications, the fabric is preferably coated with PTFE
(polytetrafluoroethylene) and for lower temperatures, the fabric is
preferably coated with polyolefins. Such coatings in combination
with the fabric material allow for the vessel to be flexible while
at the same time holding various chemicals under heated, cold
and/or pressure situations. While specific materials are outlined
herein, other materials may be used which exhibit similar
properties. It is advantageous if the materials which comprise the
vessel are disposable via incineration, although in some
circumstances, especially where the septum is made of metal, cast
or machined to provide conduits therein that the septum is
reuseable.
In FIG. 4, the inner chambers of a mixing vessel 10 are shown,
namely an upper chamber 11 and a lower chamber 12. Dividing the
chambers is septum 500, which has a perforations region 400. When
vessel 10 is filled up to a certain level (typically approximately
1/2 full) and the gas (or at least most of it) is expelled.
Perforations 400 allow for the material to pass between the upper
and lower chambers 11, 12. The open area of the perforations,
expressed as a percentage of the total area of the septum, can
vary, but is typically between e.g., approximately 10 and 90% or 30
and 75%, more typically between 40 and 60%, and preferably between
45 and 50%, such as 45%. Of course, it should be understood that
the preferred open percentage depends upon various parameters, such
as the viscosity of the materials and the sensitivity of the
material to be treated. It is within the scope of the invention to
modify such open area by changing the size and shape of the
perforations, so as to vary the open area to an amount greater or
lesser than the preferable range. In addition, as shown in FIG. 16,
flexible thin walled tubes 1601 with flared ends can be inserted
into the perforations of septum 500 during preassembly of the
septum and can move up and down relative to the septum 500. The
tubes 1601 can be made of flexible material to allow easy insertion
into the perforations of septum 500 by simply bending the flared
ends and forcing them into the holes. By making the tubes of
slightly smaller diameter than the holes in septum 500 free
movement of tubes 1601 is permitted relative to septum 500. The
provision of such tubes 1601 permits travel of the tubes down
through the holes in septum 500 during an upstroke in the direction
of arrows 1602 of the septum 500 to expose solute to the jets 1603
for a longer duration for more efficient erosion and scouring of
the bottom of vessel 10. This is particularly effective where a
precipitate or solid component is present on the bottom of vessel
10.
Alternative designs to cause swirling is shown in FIGS. 17, 18 and
19. As shown in FIG. 17, septum 500 is provided with perforations
1701 which are angled at other than 90.degree. with regard to
septum 500. The motion of the septum will force the fluid through
the perforations 1701 at an angle such that a swirl is
automatically introduced in the top chamber during a down stroke of
the septum 500 and in the bottom chamber during an upstroke. The
presence of swirl greatly enhances dispersion and the opportunity
to increase reactivity of reactants, solvent, etc. in the vessel
10. FIG. 18 shows an alternative manner of inducing swirl by
tilting septum 500 from forces 1801, 1802 applied to the opposite
ends of septum 500. During tilting, a sloshing mixture is imparted
to the contents of the vessel due to controlled periodic tilting.
The periodic tilting motion can be performed by simply forcing two
activators of the septum 500 to oscillate at a 45.degree. to
90.degree. out of phase arrangement.
FIG. 19A illustrates a further alternative to induce the contents
of the vessel 10 through perforations in septum 500 by rocking the
vessel 10 as shown by arrows 1901, 1902. A conventional
rocking-type system is illustrated in of U.S. Pat. No. 6,544,788,
herein incorporated by reference in its entirety.
As shown in FIG. 19B, one embodiment of the present invention
consists of a plastic bag 1910 that can be partially (10% to 80%)
filled with, e.g., culture media and cells. The remainder of the
chamber is typically inflated and can have a gas filled headspace
1912. Oxygen, necessary for cell metabolism, can provided by air
(or other oxygen enriched gas) can be introduced through
sterilizing inlet filter 1913 (not shown), or otherwise introduced
before the container is sealed. Exhaust air can be vented from the
chamber, (if necessary) through an exhaust filter 1914 (not shown).
This filter 1913 can be modified to ensure that no cells can be
released as an aerosol from the bioreactor. It can also be use to
ensure that in the event of bag depressurization, backflow through
the vent 1914 would not result in contamination. The bag 1910 can
attached to a rocking platform 1915 that can moves back and forth,
e.g., across pivot point 1916. Typical rocking speeds can be at any
rate from 5 to 100 rocks per minute, typically 5 to 75 rocks per
minute and preferably 10 to 30 rocks per minute through any angle,
typically 1 to 25 degrees from the horizontal, typically 2 to 15
degrees, and preferably 4 to 10 degrees from the horizontal.
The perfusion filter 1920 can floats on the liquid surface. It is
preferably constructed such that it has essentially neutral
buoyancy. The lower surface of the filter 1920 can include a liquid
permeable membrane 1921 (not shown) that is submerged in the liquid
during use. This membrane 1921 preferably has a porosity such that
cells cannot pass through it. By applying suction on a the flexible
filtrate tube 1922, cell-free filtrate is drawn up into the filter
1920 and removed from the bioreactor. The flexible tube 1922 is the
only attachment point of the filter 1920 and so the filter 1920 is
free to move on the liquid surface. The rocking motion of the
bioreactor can move the filter back and forth rapidly across the
liquid surface. This rapid tangential movement of the filter 1920
on the surface can be used to exert a scouring action and keeps the
filter 1920 from clogging.
The perfusion filter 1920 preferably includes a filtration
membrane, made of a material of suitable porosity to retain cells.
In the preferred embodiment, the filter membrane can be a sintered
porous polyethylene sheet with a mean pore size of 7 microns (Porex
T3). The porous polyethylene has the advantage of a very smooth
surface and is electrically charged such that the cells are
inhibited from attaching to the surface of the filter 1920. The
polypropylene material can also be easily heat welded. Other
suitable plastics such as nylon and polyethylene could also be
used. The filtration membrane is preferably heat welded to a
non-porous upper layer. In the preferred embodiment this layer is
made of clear polyethylene film. A hose barb port can be attached
to the upper layer so that the filtrate tube may be easily
attached. A polyethylene mesh can be placed inside the filter 1920
to prevent the filtration membrane from being sucked flat against
the upper layer and choking off flow. The entire filter assembly
1920 can be sealed by a thermally welded seam.
The filter 1920 is placed inside the bioreactor bag and a harvest
tube 1922 is connected using flexible tubing so that the filtrate
can be removed from the bioreactor. It is preferable that this
tubing be flexible enough to permit the filter 1920 to move freely
on the liquid surface. The filter 1920 and bioreactor bag can be
sterilized in situ by gamma radiation. The system is extremely
simple to use--the bag 1910 is filled with growth promoting sterile
nutrient media. Cells can be added and the bag 1910 placed on the
rocking platform 1915. The bioreactor is rocked and aerated to
promote cell growth. Once the cell density has reached the desired
level (typically 2 to 4 million cells/ml) perfusion operation is
started. Cell-free filtrate is withdrawn through the perfusion
filter 20 and collected. Equal amount of feed is added to provide
nutrients. The perfusion operation puts the cells into a
steady-state operation and can be extended for many weeks.
Perfusion operations require that nutrients be fed at a slow rate
to the bioreactor. At the same time, liquid must be removed from
the bioreactor to keep the volume reasonably constant and to remove
toxic metabolic byproducts. In the case of secreted products, this
harvest liquid may contain the product to be purified. In perfusion
operation it is critical that cells not be allowed to leave the
bioreactor. Otherwise, the cell concentration in the bioreactor
will drop due to washout of the cells. In practice, a small amount
of cell loss (<10%) is tolerated in order to remove dead and
dying cells and to promote a low level of cell regrowth. Although a
single filter 1920 is shown, multiple filters, such as one on
either side of the septum or multiple filters on the same side of
the filter may be used.
A preferred perfusion control system according to the present
invention is shown in FIG. 19B. The bioreactor is typically fed
nutrients from a feed container 1932 that can be suspended from a
hook equipped with a weight sensor 1931. The rate of feed can be
controlled by a feed pump 1933. This feed pump 1933 can be operated
intermittently by a controller 1950 pumping feed into the
bioreactor via inlet port 1930. The controller 1950 can turn the
feed pump 1933 on until preset weight of feed, as measured by loss
in weight of the feed container 1932, is delivered into the
bioreactor. Next, the harvest pump 1934 can be switched on. This
pump 1934 can be use to suck filtrate up through the perfusion
filter 1920 and pump the collected material into a collection
vessel 1935, which is also typically suspended from the same hook
as the feed container 1932. The controller 1950 typically runs this
pump 1934 until the net weight loss measured at the hook is zero,
i.e., until the mass of the material added to container 1935 equals
the mass of the material removed from container 1932. This ensures
that the amount of harvest removed equals the feed added to the
bioreactor. The cycle can then be repeated. The frequency of
cycling can be adjusted to give the desired overall perfusion rate.
The cumulative amount of feed added and harvest removed can be
easily calculated from the cycling of the weight sensor 1931. This
simple mechanism provides complete control of feed rate and
harvest. Alarms can be programmed to warn of pump or filter failure
to prevent the loss of valuable cells.
A more detailed view of a typical septum 500 according to the
invention is shown in FIG. 5. The outer ring 501 of the septum has
located inside it a generally flat piece of fabric 502. The portion
of septum 500 that interacts with the inner chambers of the vessel
has a series of perforations or holes 504, which form the
perforations region. Each hole 504 is not designed to filter
material, but is intended to create a flow pattern and generate
turbulence as the material passes through septum 500 which aids in
the mixing and other processes using the septum. The shape, size,
and edge properties (along with septum velocity) can be modified to
change the fluid shear properties (e.g., low for cell matter, and
high for chemicals requiring aggressive mixing).
A mixing operation of vessel 10 is shown in FIGS. 6A, 6B and 6C.
Generally, material 1 to be mixed is introduced into vessel 10 via
an entrance tube 570 located in upper disk 510. Vessel 10 is filled
up to about its midway point of its full volume to allow for
flexing of the vessel. Following the introduction of material 1
into vessel 10, entrance tube 570 is closed. For most operations, a
vacuum is then applied to vessel 10 via vacuum tube 550 to remove
excess air and bring upper disk 510 down against the material 1
level in the vessel. The removal of the air creates a run length of
wrinkles in the vessel sidewalls that allows septum 500 to move
relative to each of upper and lower disks 510 and 520. The removal
also prevents gas entrainment is the mixing process. However, some
operations allow for the excess air and other gases to remain in
vessel 10. For example, some reactions require the absence of air
or oxygen and, thus, an inert atmosphere (such as nitrogen, a noble
or other inert gas) can be placed in the vessel 10 both during
filling and during subsequent mixing or other use of the vessel
10.
In one embodiment, the mixing operation comprises a motion of
septum 500 between two positions as shown in FIGS. 6A and 6B. In
the first position, septum 500 is pulled nearly into contact with
upper disk 510 allowing for nearly all of material 1 to be in the
lower chamber of vessel 10. The lower wall 540 is tightened as a
result and holds the bulk of material 1. Such is shown in FIG. 6A.
A perspective view of vessel 10 at this position during a mixing
motion is shown in FIG. 6C where the vessel is half full of
material 1 with the gas partially removed and lower wall 540 is
tightened while upper wall 530 is wrinkled as septum 500 is pulled
upwards. The motion can be generated by any means, such as manual,
pneumatic, hydraulic, magnetic or any other electromechanical
system, such as by pistons 2020, 2021 located 180.degree. apart and
connected to the periphery of septum 500.
In the embodiment of FIG. 20, upper disk 510 and lower disk 520 are
reaction plates and septum 500 is attached to a center drive
actuator (shown as pistons 2020 and 2021). Herein, flexible vessel
10 is mounted to the reaction plates 510 and 520 as well as to the
drive actuator plates. As shown in the various figures, each of
these plates may be secured to the material of the vessel 10 by a
deadman. Alternatively, the septum 500 may be connected to the
vessel via a rigid, hard connection. In order to allow independent
squeezing and expanding of the plates, reaction plates 510 and 520
may be provided with separate motion. Furthermore, by mounting
septum 500 on a separately actuated drive mechanism, greater
flexibility is provided, allowing pressure against one or both
reaction plates 510 and 520. Such further flexibility includes the
application of various processing parameters, e.g., force, range of
motion, temperature, and vacuum/pressure. Moreover, fill/discharge
tubes 2025 may be included to allow for easy filling or emptying of
the vessel. While vessel 10 is shown with two fill/discharge tubes
on top and one on the bottom, it is within the scope of the
invention to vary the numbers and location of the various tubes
2025. For example, the tubes 2025 may be placed on the sides of the
vessel in any combination. Additional mechanisms may be provided to
rotate the vessel in one, two or all three axes. Because the
mechanical actuator may be separated from the contents of the
vessel, CIP/SIP is not needed. Finally, the mechanical actuator may
be programmed to accomplish any number of functions, such as
mixing, reacting, and filtering.
Then septum is pulled downwards towards lower disk 520. During this
operation, both the upper wall 530 and lower wall 540 would be
wrinkled. As it is pulled, material 1 begins to pass through holes
540 in the perforation region 400 and begins to enter the upper
chamber of vessel 10. Holes 540 create a rapid flow of material 1,
forcing the mixture of the constituents of material 1 and then
injecting material 1 into the upper chamber to create a turbulent
flow in the material, further aiding mixing of the constituents.
Once septum 500 is pulled completely down near lower disk 520,
nearly all of material 1 is located in the upper chamber. This
situation is shown in FIG. 6B.
The mixing process is then continued by pulling the septum upwards
towards upper disk 510, which is a reverse operation to that
described above, and results to achieve the situation shown in FIG.
6A again. A full mixing operation comprised of multiple operations
of this movement of septum 500 up and down will thoroughly mix the
constituents in material 1. Following completion of the mixing
process, the material can be either stored within vessel 10 or
discharged into another location.
In an additional embodiment, septum 500 can be used as a conductive
heating/cooling source to heat or cool material 1 located within
vessel 10. In FIGS. 7A and 7B, a temperature tube 703 is run
through the middle layer of fabric of septum 500. Tube 703 may be a
simple flute hole extending into septum 500. Tube 703 may also be a
chamber formed throughout septum 500, in between upper septum layer
705 and lower septum layer 706. A baffle 704 is then connected to
an outer portion of septum 500 to divide temperature tube 703 into
two channels or chambers, an upper channel 708 and a lower channel
709, except at a connection hole 707, which communicates the upper
and lower channels. At an outer fabric ring 505 of septum 500, a
temperature fluid entrance tube 701 is connected to the septum and
communicates with one channel of temperature tube 703 and a
temperature fluid exit tube 702 is connected to the other channel
of the temperature tube. Fluid introduced into temperature fluid
entrance tube 701 travels along upper channel 708 through
temperature tube 703, down through connection hole 707 into lower
channel 709 through the temperature tube and exits at temperature
fluid exit tube 702. Such creates a fluid circuit within septum
500, as shown in FIG. 7B. If a hot fluid in sent through the
circuit, the fluid will heat up septum 500, and septum 500 will
transfer the heat into material 1 in vessel 10. Likewise for cold
fluid sent through the circuit. While this conductive
heating/cooling operation may be operated alone, it is preferably
operated in conjunction with a mixing motion of vessel 10 as
outlined above to provide a more effective process. The conductive
heating/cooling process may also be operated simultaneously with a
mixing operation.
As an alternative to the fluted heating system as disclosed above,
septum 500 may have a heating/cooling system extending throughout
its inner chamber, which is shown in FIGS. 7C and 7D. In such a
design, septum 500 comprises a pair of parallel rigid plates 730
and 740 in lieu of the flexible material of the other embodiments.
Running between rigid plates 730 and 740 is a baffle plate 720
which creates a septum upper chamber 731 and a septum lower chamber
741 between the rigid plates. In a process of heating or cooling,
fluid enters septum 500 via the temperature fluid entrance tube 701
and passes into septum upper chamber 731. The fluid spreads
throughout septum upper chamber 731 which allows the temperature of
the fluid to dissipate into the material in vessel 10. The fluid
then passes through central passage 710 and into septum lower
chamber 741, where the fluid again spreads throughout the septum
lower chamber which allows the fluid temperature to further
dissipate into or out of material 1 in vessel 10. The fluid then
exits septum 500 through temperature fluid exit tube 702 where the
fluid can be recycled and recirculated through the septum. This
process can also be completed while performing a mixing or other
process. The plates 730 and/or 740 can be formed of metal, plastic,
ceramic, composites or similar materials.
As a further alternative to the conductive heating processes
described above, a pair of reaction plates 900 and 910, as shown in
FIG. 8, e.g., can be attached to vessel 10 against upper and lower
disks 510 and 520 may provide, e.g., microwave heating during
mixing or other operations. Reaction plates 900 and 910 may have
microwave emitters incorporated therein or attached thereto which
can be used to heat up material 1 inside the chambers of vessel 10
through either the top or bottom surface of the vessel. Inductive
heating of the septum can also be achieved through the use septums
made of metal.
FIG. 8 additionally shows a frangible bag 890 which can contain
material. By utilizing a frangible bag 890, the material can be
maintained separated from the septum and any other material. Only
upon rupturing of the bag 890 is the material contained therein
released. Such rupturing may be accomplished by physical pressure
(such as squeezing), chemical, heat or any other means. Such
frangible bags 890 may be utilized in any embodiment described
herein. Similarly, the septum 500 may be provided with a frangible
element, such as a membrane, which essentially accomplishes the
same purpose as the bag 890. Upon rupturing of the membrane, can
the contents of the vessel contact each other and the septum. Such
a membrane may be ruptured in the same or a different manner than
the bag 890.
In another embodiment, vessel 10 may be operated as a bioreaction,
such as fermentation, apparatus. The apparatus has additional feed
tubes 800 and 810 interconnected to septum 500 and
intercommunicating to the inner chambers of vessel 10, as shown in
FIGS. 9A and 9B. Feed tubes 800 and 810 communicate, at the outer
fabric ring 505 of septum 500, with inner feed tubes 801 and 811,
respectively, which in turn communicate with the inner chambers of
vessel 10 through feed holes 802 and 812, respectively. At or near
feed holes 802 and 812, within inner feed tubes 801 and 802 or even
within feed tubes 800 and 810, are one way valves for preventing a
back wash of material from the inner chambers out the feed tubes.
Such features provide the ability to add material, chemicals or gas
into the chamber during mixing, reacting or heating operations of
vessel 10.
The process of bioreaction begins with a media pre-mixing, heating
and cooling, which may take place within vessel 10 or other similar
vessels. Then the correct proportions of media and seed are
introduced into vessel 10 via the method described above. Then it
is determined whether a gas head is desired within the chambers of
vessel 10, for example, introduce or leave a gas head if needed for
an aerobic reaction, remove head if anaerobic. If no gas head is
desired, then the gas head is pulled from vessel 10 via the method
described above. The entire material 1 is then mixed, cooled and
heated as needed using the methods and apparatus described above
and continued as necessary.
Addition of make-up solutions, optionally including a gas, are then
added as needed through feed tube 800 and into the chamber through
inner feed tube 801 and feed hole 802. These solutions can be
metered in septum 500 or before they are introduced into the
septum. Such process allows for efficient introduction and mixing
with minimal agitation. At the proper point, the lysing solution
can also be added into the chamber via feed tube 810, inner feed
tube 811 and feed hole 812. These solutions can also be metered
through the septum or externally, optionally through individual
feed tubes. Following the process, the meter solutions can be
either stored within vessel 10 or discharged into another
location.
In another embodiment, vessel 10 operates as a reactor for
constituents of material 1. As mentioned above, vessel 10 is
provided with a pair of reaction plates 900 and 910. These plates,
in addition to providing a heat source for vessel 10, also move
with respect to each other to provide pressure against vessel 10,
as shown in FIG. 8. The pressure effectively squeezes vessel 10 to
aid in promoting a chemical reaction, while still allowing mixing
to occur.
The process begins by adding in constituents, such as separated or
pre-mixed powders, solvents, etc. along with catalysts, into the
chamber of vessel 10 in the method as described above and in
reference to FIGS. 8, 9A and 9B. If needed, as also described
above, gas head may be removed via vacuum tube 550. The gas head
can also be maintained if needed. Once these constituents are added
in and vessel 10 is sealed, reaction plate 900 and 910 begin to
apply pressure and begin to squeeze the vessel. Catalysts may be
added by introducing them through feed holes 802 and 812. Catalysts
may also be captured on the center septum such that they would
contact material 1 during a mixing operation. Catalyst may also be
introduced along the perforations in the septum, especially when
the system is made of metal. The constituents along with the
catalysts are forced together to a predetermined pressure that is
required for the specific process or material desired.
Additionally, the material may be heated or cooled in the manner as
described above via either septum 500 or the microwave or other
heaters associated with reactors 900 and 910. The mixing process
may also be performed simultaneously with the pressure to aid in
the reacting process. Following completion of the reaction process,
the material can be either stored within vessel 10 or discharged
into another location.
In a further embodiment, vessel 10 can have incorporated therein a
micro/ultra-filtration system. As shown in FIGS. 10A, 10B and 10C,
septum can have a plurality of filter regions and mixing regions.
In side the chamber of vessel 10, the fabric of septum 500 has
various filter regions, and within each region, septum 500 has on
its outer surface a micro-porous coating (filter) 1070 for
filtering material, a structural fabric 1055 beneath the coating
and a spacer fabric layer 1080 inside these layers which allows for
trapping and movement of filtered material. Outside vessel 10, in
the region of the outer fabric ring 505, septum 500 has a
non-porous sealant layer 1050 re-enforced with a structural fabric
1060 for preventing leakage of filtered material from outside
septum 500 and another spacer fabric layer 1080 for trapping and
movement of filtered material. The spacer fabric layers 1080
effectively provide a transit tube by which the particulate is
moved to outside vessel 10.
Communicating with spacer fabric layer 1080 is a filter tube 1030
that is further connected to a vacuum source 1000 which provides a
vacuum through the system to pull in particulate from material 1,
through the micro-porous coating 1070, into the spacer fabric layer
1080 and into and through the vacuum. Vacuum 1000 then deposits
filtered particulate 1020 into a filtrate container 1010. A vacuum
of 11 to 13 psi provides a generally sufficient vacuum for
microfiltration, however, other vacuums may be used depending on
the application.
For an effective filter operation, a mixing process may be used in
conjunction with the vacuum applied across the filter. The mixing
process creates turbulent flow conditions and performs a
recirculation function as outlined above which keeps the level of
particulate even throughout the material 1 in vessel 10 and
prevents fouling of the micro-pores by larger particles. As the
particulate in the material 1 nears moving septum 500 during a
mixing operation, the vacuum will pull it from the material into
the vacuum system. Alternatively, the pressure drop across the
micro-porous coating can be achieved by pressurizing material 1 in
vessel 10 using reaction plates 900 and 910, describe above, to
squeeze vessel 10.
As an alternative to this filtration system, vessel 10 may have
incorporated therein a filter septum 1300 in addition to septum
500, as shown in FIG. 13A. Rather than a septum having the features
described above, filter septum 1300 has a micro-filter 1310 located
therein to filter out a predetermined material. The filter septum
1300 is preferably located between septum 500 and lower disk 520,
as shown in FIGS. 13B and 13C, but other locations are
possible.
A preferable process of filtration using filter septum 1300 begins
by lowering filter septum 1300 until it is adjacent to lower disk
520, as shown in FIG. 13B. Then other process described herein may
be performed, such as mixing, heating/cooling, reacting and/or
fermenting. Following these processes, septum 500, can be operated
in a mixing mode while filter septum 1300 is then pulled up while
septum 510 is held stationary, e.g., until it is adjacent septum
500 and both septums are pulled adjacent to upper disk 510. This
creates a pressure that forces material 1350 through micro-filter
1310, leaving a retained material 1356 above filter septum 1300 and
a residual material 1355 below. The continued mixing operation of
septum 500 during the filtration provides turbulent flow conditions
needed for efficient filtration.
In another embodiment of the invention, vessel 10 can be used to
express slurry 1150 into a cake. As shown in FIGS. 11A through 11E,
vessel 10 has a flexible spacer fabric layer 1110 and a cake fabric
filter 1120 which provides means to filter the cake from the slurry
1150 or to filter the cake from a cleaning agent. Additionally,
vessel 10 has an isolation film 1130 with a tear bead 1131. The
isolation film allows for the mixing, heating/cooling, reacting
and/or fermenting to create slurry in the chamber of vessel 10
without interfering with cake filter 1120 and exiting out slurry
tube 1100.
A bag out sleeve 1140 provided along side wall 530 which allows a
user to reach into the chamber of vessel 10 and pull tear bead 1131
and remove isolation film 1130 from the surface of spacer fabric
layer 1110 and cake fabric filter 1120.
A process of creating a cake using vessel 10 is shown in FIGS. 11B
and 11C. First, slurry is created inside the chamber of the vessel
10 using a process outlined above or is placed into the chamber via
entrance tube 570 (FIG. 6A) and any gas head may be vacuumed out
via vacuum tube 550 (FIG. 6A). Septum 500 is moved downward into
contact with lower disk 520. Next, isolation film 1130 is removed
by pulling tear bead 1131 via bag out sleeve 1140 to allow
filtration of slurry 1150.
To begin expressing a cake from slurry 1150, septum 500 and lower
disk 520 are moved upwards towards and against upper disk 510. Such
motion forces the slurry into cake filter 1120 which prevents cake
particulate from passing and allows a slurry discharge to exit the
chamber of vessel 10 through slurry tube 1100. The slurry discharge
is collected in a discharge collector 1101. Lower disk 520 and
septum 500 will continue movement upwards until all possible slurry
discharge is removed from now forming cake 1155, as shown in FIG.
11C.
Following an expressing step, it may be desired to clean cake
before any further processing. In such a process, a cleaning
solution is injected into the chamber of vessel 10 from cleaning
apparatus 1102 and through slurry tube 1100 while simultaneously
pulling septum 500 and lower disk 520 downward and away from upper
disk 510. The chamber will now have cake particulate and a cleaning
solution therein. A mixing motion may then be performed to
thoroughly clean and mix the cake particulate and the cleaning
solution into cleaning slurry 1151. Heating or other process may
also be performed.
Once the cake particulate is thoroughly cleaned, the cleaning
solution is removed from the chamber by pulling up septum 500 and
lower disk 520 towards upper disk 510. The cleaning solution is
forced through cake filter 1120 which filters out the cake
particulate. The cleaning solution is then collected in the
discharge collector 1101. Upon full removal of the cleaning
solution, a cleaned cake 1155 is formed in the chamber of vessel
10.
Following creation of cake 1155, lower disk 520 is retracted to its
lower most position away from upper disk 510. Upon a vibration of
the upper disk area, the cake 1155 will fall to the bottom of
vessel 10 adjacent lower disk 520. Following this process the cake
can be either stored within vessel 10 or discharged into another
location.
Following a process of creating cake 1155 or introduction of the
cake into vessel 10, the vessel may also be used to dry the cake
using components of the vessel outlined above with an additional
drying septum 1220 having a wire grid and/or a fabric grid
incorporated therein, as shown in FIGS. 12A through 12D. While an
additional septum may be used, its features may be incorporated
into septum 500 for use in vessel 10. For simplicity sake, whether
an additional septum is used or drying septum 1220 is used, FIGS.
12B through 12D will show only drying septum 1220.
The drying may be completed using two separate systems of drying.
First, reaction plate 900 may be located adjacent below the upper
or lower disks 510 and 520. Reaction plate 900 below lower disk 520
is shown. Reaction plate 900, as described above, has incorporated
therein a microwave heater which can be use to heat cake 1155
located within the chamber of vessel 10. Additionally, a gas may be
introduced into vessel 10 via gas tube 1210 to interact with cake
1155 and then the moisture laden gas exits vessel 10 via gas exit
tube 1220.
A process for drying cake 1155 is shown in FIGS. 12B through 12D.
Cake 1155 is introduced into vessel 10 via any means previously
disclosed or cake is formed by the process disclosed above. Drying
septum 1220 is placed adjacent lower disk 520 and both are pulled
away from upper disk 510, as shown in FIG. 12B. Microwave heat is
then applied to cake 1155 by reaction plate 900. Alternatively,
heated gas can also be introduced via gas tube 1210, passed through
cake 1155 and exits gas exit tube 1220. After a predetermined time,
drying septum 1220 is pulled up to upper disk 510 away from lower
disk 520, allowing cake 1155 to be sifted through the drying
septum, as shown in FIG. 12C. After a second predetermined time,
vessel 10 is then rotated over as shown in FIG. 12C. Again after a
predetermined time, drying septum is pulled up, this time toward
lower disk 520 away from upper disk 510. After a predetermined time
again, vessel 10 is rotated again, returning it to the orientation
shown in FIG. 12B. This process may be repeated as necessary to dry
cake 1155. Following this process the dried cake can be either
stored within vessel 10 or discharged into another location.
To remove material, cakes, etc., vessel 10 is provided with a
discharge chute that allows removal from either upper disk 510 or
lower disk 520, preferably lower disk 520. The main components of a
discharge chute located on lower disk 520 are shown in FIGS. 14A
and 14B. A tear panel 1421 having a generally round or other
two-dimensional shape is located on a part of lower disk 520. A
circumferential cord 1422 surrounds tear panel 1421 forming a
buffer between lower disk 520 and tear panel 1421. A tug on a tear
bead 1420 pulls cord 1422 and panel 147 from the surface of lower
disk 520. Covering the entirety of tear panel 1421 and attached to
lower disk 520 is a discharge bag 1410 in a folded condition.
Covering the entirety of discharge bag 1410 and also attached to
lower disk 520 is a bag cover comprising a anchoring portion 1400
and a loop 1401 located thereon holding in place a cover 1401.
Cover 1401 may be a panel or it may be a strap for holding
discharge bag 1410 in a flat orientation. Loop 1402 surrounds cover
1401 if the cover is a panel and is activated to allow removal of
the cover. Loop 1402 may be a becket loop, however, loop 1402 may
also be simply a connection means if cover 1401 is merely strap.
Loop 1402 adjoins cover 1401 and the rest of bag cover 1400.
The process of removal of material from inside vessel 10 begins
with an activation of loop 1402 to remove cover 1401. Loop then
hangs down from lower disk 520, as shown in FIG. 14B. The removal
of cover 1401 allows access to discharge bag 1410. Discharge bag
1410 is extended out of its folded condition to allow room to
accept material from vessel 10. Once discharge bag is fully
extended, a bag out sleeve 1411 is further extended from discharge
bag 1410. A user pushes bag out sleeve 1411 into the chamber of
discharge bag 1410 and reaches for tear bead 1420. A pull on tear
bead 1420 causes cord 1422 and hence tear panel 1421 to be removed
from lower disk 520. Tear bead 1420, cord 1422 and tear panel 1421
are then pulled away from lower disk 520 and into bag out sleeve
1411 as shown in FIG. 14B. This process then exposes material in
vessel 10 to discharge bag 1410. Material may then flow directly
into discharge bag 1410 or vessel 10 may be kneaded sufficiently to
remove all material. Discharge bag 1410 my then be removed from
vessel 10 for transport or storage of the material. The bottom of
discharge bag 1410 may also have a connection port to another piece
of equipment, if needed.
Although each of the unit operations shown in a typical chemical
process of FIG. 2 can be separately carried out in a vessel 10,
according to the present invention a single vessel can perform
multiple unit operations. Thus, as shown in FIG. 22, the process of
FIG. 2 has been divided into 5 subprocess or modules shown by the
dotted lines as: 1. Bioreactor module; 2. Microfiltration module;
3. Microfiltration module after Lysis; 4. Ultrafiltration module;
and 5. Separation module.
As shown in FIGS. 23A-23E, the bioreactor module comprises a series
of septums 2001, 2002, 2003, 2004, 2005, etc., each in a separate
enclosed volume from a previous chamber created by removable
isolator films 2012, 2013, 2014, 2015, etc. A tear out bead is
built into such isolator films, such that when it is desired to
change the unit operation, i.e., to change from a mixing operation
to a filtration operation, the isolator film is ruptured permitting
the mixed components to be contacted by a further septum, e.g.,
2003. Other unit operations can be achieved by providing different
septums and other isolating films so that progressive unit
operations are all conducted in a single vessel 2013, as shown in
FIGS. 23B-23E.
FIGS. 23A-23E depict a typical operation of an embodiment of the
invention. This operation is described as a preferred operation,
however, the invention should not be limited to the description of
this operation. With reference to FIG. 23A, media or seed is
charged to the bioreactor through the top, and any gaseous head is
removed by moving septum 2003 against septum 2001. Through septum
2002, the contents are stirred, heated, entrained, or measured
(such as oxygen percentage) in a pH buffer. Exhaust carbon dioxide
is released through the top of the bioreactor. Any replenishment
media can be added through the top of the bioreactor, causing
septum 2003 to move away from septum 2001 to allow for, e.g.,
growth in volume in the reactor.
In order to convert the bioreactor from its initial configuration,
isolator film 2013 is removed, preferably through a bag out sleeve
(not shown) to expose septum 2003. This converts septum 2003 from a
bottom septum into a microfilter septum. Thereafter, the bag out
sleeve is heat sealed and the isolator film 2012 can be
discarded.
A typical microfiltation is shown in FIG. 23B, to follow the steps
described with reference to FIG. 23A. A diafiltration buffer is
added through septum 2002. By moving septum 2002 vertically, the
contents are mixed by a turbulent flow. Septum 2003 (now a
microfilter septum), is moved against septum 2001, creating
pressure differential (.DELTA.P) across the septum 2003 forcing
filtrate into a space B. The retentate is removed from a space A by
collapsing septum 2003 and 2002 into septum 2001. Isolator film
2015 is pulled out through a bag out sleeve 2125, converting septum
2005 from a bottom septum into another microfilter septum.
Thereafter, the bag out sleeve is heat sealed and the isolator film
2015 can be discarded.
FIG. 23C depicts another microfiltration which, in this embodiment,
follows the microfiltration shown in FIG. 23B. A lysis buffer is
added through septum 2004, which is actually a mixing septum.
Turbulent flow to mix is provided by relatively moving septum 2004
vertically. Thereafter, septum 2005 is moved against septum 2001 to
create .DELTA.P across septum 2005, forcing filtrate into a space
C. Retentate is removed from space B by collapsing septums 2005 and
2004 into septums 2003, 2002 and 2001. Isolator film 2017 is pulled
out through a bag out sleeve 2117, converting septum 2007 from a
bottom septum into an ultrafiltration septum. Thereafter, the bag
out sleeve is heat sealed and the isolator film 2017 can be
discarded.
FIG. 23D shows an ultrafiltration, which in this embodiment,
follows the microfiltration depicted in FIG. 23C. Turbulent flow,
to mix the contents, is created by moving septum 2006 vertically.
Moving septum 2007 against septum 2001 creates .DELTA.P across
septum 2007, forcing filtrate into a space D. Retentate is removed
from space C by collapsing septums 2007 and 2006 into septums 2005,
2004, 2003, 2002 and 2001. Isolator film 2018 is pulled out through
a bag out sleeve 2028, converting septum 2008 from a bottom septum
into an separator septum. Thereafter, the bag out sleeve is heat
sealed and the isolator film 2018 can be discarded.
FIG. 23E shows a separation, which in this embodiment, follows the
ultrafiltration depicted in FIG. 23D. Septum 2007 is moved slowly
vertically until adsorption is complete. By collapsing septum 2009
against septum 2001, most of the material not absorbed is removed.
Solvent is added through septum 2008 to bring the concentration to
just below that necessary for desorption of the desired product.
Through septum 2008, solvent and waste are removed from the
bioreactor. Solvent is then added again through septum 2008 to the
level to desorb the desired product. Thereafter, the solvent and
the desired product are flowed out of the system through septum
2008.
Additionally, the vessels can be mounted in parallel by flexible
and/or disposible piping which can be crimped off. The flow between
the various vessels can be controlled, for example, by a
peristaltic pump, such that metered amounts of solutions can be
charged into the appropriate vessel. For example, the
micofiltration system of FIG. 23B can be connected via flexible
piping to a diafiltration buffer vessel on an inlet side and a
containment vessel for the retentate on the outlet side. Such a
system allows for containment of discharged waste as well as the
product resulting from the processing, as well as completely
contained charging, processing, discharging, sampling, sensing and
storage.
The invention can also be used for chemical separations, such as
solid phase extractions, wherein separation is traditionally based
upon subtle differences in the hydrophobic attraction of the
materials being separated. Small adsorbent particles are contained
in a bed within a movable center septum. By moving the septum
vertically, recirculation is achieved by moving the septum through
the material. A preferred process for performing a solid phase
extraction is as follows: (1) the material to be separated is
charged into the vessel; (2) any gas volume is removed by
collapsing a top septum of the vessel down to the level of the
liquid; and (3) the septum is slowly raised and lowered through the
material until the separation is complete. By such a system, the
material moves through the adsorbent bed twice per cycle.
Thereafter, the procedure follows the steps described with
reference to FIG. 23E, separation. By this system, the variable
volume feature allows the system to be run with less solvent.
The invention may also be used to perform a powder blending
operation. According to a preferred embodiment, a center septum is
initially at the bottom of a vessel, before the powders are added
through the top. Air flow is used to create a fluidized bed, in
from both the bottom of the vessel and through the septum, whereby
the air is filtered out of the tip. Once the bed is fluidized, the
septum can be moved vertically to mix or blend the contents.
Although the present invention has been described and illustrated
in detail to a specific design and structure, such explanation is
to be clearly understood that the same is by way of illustration
and example only, and is not to be taken by way of limitation.
Other modifications of the above examples may be made by those
having ordinary skill in the art which remain within the scope of
the invention. In the disclosure above, vessel 10 has been shown in
this disclosure to be of a cylindrical shape, however, various
other shapes and configurations are possible using the teachings of
this invention. For example, rather than using a cylindrical-shaped
vessel having, the vessel may have other shapes, such as those
shown in FIGS. 15A through 15C, wherein a taper can be made in the
side wall of the vessel to alter the effect of processes outlined
above. The shape used should be chosen with the nature of the
process required. In FIG. 15D there is shown a further modification
of the vessel having a rectangular box design. Other
three-dimensional designs are further possible, such as triangular
boxes, hexagonal boxes, and other polygonal boxes and
configurations. As shown in FIG. 21, the shape of the bottom of
vessel 10 affects the speed of mixing, with a domed shape being
preferable to a flat or dish-shaped bottom. Additionally, static
mixers may be placed in perforations 400 to increase the degree of
mixing.
Further, the vessel need not necessarily have an accordion type of
structure, which is shown and described herein, it may rather be
more of a pivoting structure, as is shown in FIGS. 15E and 15F. In
such a structure, upper disk, lower disk and septum are all pivoted
about a pivot axis.
It should be apparent from this description that embodiments other
than those described above come within the spirit and scope of the
present invention. Finally, due to the construction, the vessels
can be re-used, if only for limited times. Additionally, although
the above-description has been made using a liquid, any fluid or
combination of fluids may be used in either chamber.
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